Friday, May 6, 2011

Food Reward: a Dominant Factor in Obesity, Part II

How to Make a Rat Obese

Rodents are an important model organism for the study of human obesity. To study obesity in rodents, you have to make them fat first. There are many ways to do this, from genetic mutations, to brain lesions, to various diets. However, the most rapid and effective way to make a normal (non-mutant, non-lesioned) rodent obese is the "cafeteria diet." The cafeteria diet first appeared in the medical literature in 1976 (1), and was quickly adopted by other investigators. Here's a description from a recent paper (2):

Investigators have known for decades that the cafeteria diet is a highly effective way of producing obesity in rodents, but what was interesting about this particular study from my perspective is that it compared the cafeteria diet to three other commonly used rodent diets: 1) standard, unpurified chow; 2) a purified/refined high-fat diet; 3) a purified/refined low-fat diet designed as a comparator for the high-fat diet. All three of these diets were given as homogeneous pellets, and the textures range from hard and fibrous (chow) to soft and oily like cookie dough (high-fat). The low-fat diet contains a lot of sugar, the high-fat diet contains a modest amount of sugar, and the chow diet contains virtually none. The particular high-fat diet in this paper (Research Diets D12451, 45% fat, which is high for a rat) is commonly used to produce obesity in rats, although it's not always very effective. The 60% fat version is more effective.

Consistent with previous findings, rats on every diet consumed the same number of calories over time... except the cafeteria diet-fed rats, which ate 30% more than any of the other groups. Rats on every diet gained fat compared to the unpurified chow group, but the cafeteria diet group gained much more than any of the others. There was no difference in fat gain between the purified high-fat and low-fat diets.

So in this paper, they compared two refined diets with vastly different carb:fat ratios and different sugar contents, and yet neither equaled the cafeteria diet in its ability to increase food intake and cause fat gain. The fat, starch and sugar content of the cafeteria diet was not able to fully explain its effect on fat gain. However, each diets' ability to cause fat gain correlated with its respective food reward qualities. Refined diets high in fat or sugar caused fat gain in rats relative to unpurified chow, but were surpassed by a diet containing a combination of fat, sugar, starch, salt, free glutamate (umami), interesting textures and pleasant and invariant aromas.

Although the cafeteria diet is the most effective at causing obesity in rodents, it's not commonly used because it's a lot more work than feeding pellets, and it introduces a lot of variability into experiments because each rat eats a different combination of foods.
How to Make an Obese Human Lean

In 1965, the Annals of the New York Academy of Sciences published a very unusual paper (3). Here is the stated goal of the investigators:

The study of food intake in man is fraught with difficulties which result from the enormously complex nature of human eating behavior. In man, in contrast to lower animals, the eating process involves an intricate mixture of physiologic, psychologic, cultural and esthetic considerations. People eat not only to assuage hunger, but because of the enjoyment of the meal ceremony, the pleasures of the palate and often to gratify unconscious needs that are hard to identify. Because of inherent difficulties in studying human food intake in the usual setting, we have attempted to develop a system that would minimize the variables involved and thereby improve the chances of obtaining more reliable and reproducible data.

Here's a photo of their "system":It's a machine that dispenses bland liquid food through a straw, at the push of a button. They don't give any information on the composition of the liquid diet, beyond remarking that "carbohydrate supplied 50 per cent of the calories, protein 20 per cent and fat 30 per cent. the formula contained vitamins and minerals in amount adequate for daily maintenance."

Volunteers were given access to the machine and allowed to consume as much of the liquid diet as they wanted, but no other food. Since they were in a hospital setting, the investigators could be confident that the volunteers ate nothing else.

The first thing they report is what happened when they fed two lean people using the machine, for 16 or 9 days. Both of them maintained their typical calorie intake (~3,075 and ~4,430 kcal per day) and maintained a very stable weight during this period.

Next, the investigators did the same experiment using two "grossly obese" volunteers. Again, they were asked to "obtain food from the machine whenever hungry." Over the course of the first 18 days, the first (male) volunteer consumed a meager 275 calories per day. The second (female) volunteer consumed a ridiculously low 144 calories per day over the course of 12 days, losing 23 pounds. Without showing data, the investigators remarked that an additional three obese volunteers "showed a similar inhibition of calorie intake when fed by machine."

The first volunteer continued eating bland food from the machine for a total of 70 days, losing approximately 70 pounds. After that, he was sent home with the formula and instructed to drink 400 calories of it per day, which he did for an additional 185 days, after which his total weight loss was 200 lbs. The investigators remarked that "during all this time weight was steadily lost and the patient never complained of hunger or gastrointestinal discomfort." This is truly a starvation-level calorie intake, and to eat it continually for 255 days without hunger suggests that something rather interesting was happening in this man's body.

This machine-feeding regimen was nearly as close as one can get to a diet with no rewarding properties whatsoever. Although it contained carbohydrate and fat, it did not contain any flavor or texture to associate them with, and thus the reward value of the diet was minimized. As one would expect if food reward influences the body fat setpoint, lean volunteers maintained starting weight and a normal calorie intake, while their obese counterparts rapidly lost a massive amount of fat and reduced calorie intake dramatically without hunger. This suggests that obesity is not entirely due to a "broken" metabolism (although that may still contribute), but also at least in part to a heightened sensitivity to food reward in susceptible people. This also implies that obesity may not be a disorder, but rather a normal response to the prevailing dietary environment in affluent nations.

A second study by Dr. Michel Cabanac in 1976 confirmed that reducing food reward (by feeding bland food) lowers the fat mass setpoint in humans, using a clever method that I won't discuss for the sake of brevity (4). I learned about both of these studies through the writing of Dr. Seth Roberts, author of The Shangri-La Diet. I'd also like to thank Dr. Stephen Benoit, a researcher in the food reward field, for talking through these ideas with me to make sure I wasn't misinterpreting them.

I'd like to briefly remark that there's an anatomical basis for the idea of two-way communication between brain regions that determine reward and those that control body fatness. It's well known that the latter influence the former (think about your drive to obtain food after you've just eaten a big meal vs. after you've skipped a meal), but there are also connections from the former to the latter via a brain region called the lateral hypothalamus. The point is that it's anatomically plausible that food reward determines in part the amount of body fat a person carries.

Some people may be inclined to think "well, if food tastes bad, you eat less of it; so what!" Although that may be true to some extent, I don't think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently. To me, that implies that highly rewarding food increases the body fat setpoint in susceptible people, and that food with few rewarding properties allows them to return to a leaner state.

In the next few posts, I'll describe how food reward explains the effectiveness of many popular fat loss diets, I'll describe how this hypothesis fits in with the diets and health of non-industrial cultures, and I'll outline new dietary strategies for preventing and treating obesity and certain forms of metabolic dysfunction.

65 comments:

What about the Japanese who seem to eat exremely flavorful (e.g, umami flavors) and beautifully presented foods? Their foods seem much more rewarding and tasty than cheetos or pringles, yet they stay thin.

@David: The Japanese eat rice, which is more filling and less calorie-dense than refined wheat products & chips (or French fries, as some countries call 'em). The Filipino carers in mum's nursing home told me that when they came to England and switched from rice to bread & chips, they got fatter.

As long as the market is free to produce over-tasty crap and mess with our heads by using cunning advertising techniques, I don't think that we will ever solve the obesity "problem". Government intervention isn't working too well, either.

Did they follow up what happened in the obese after they went off this flavourless very low calorie diet? I think very low calorie diets are similar to fasting in that it turns off ghrelin signaling, so its not surprising that the obese men who radically reduced their food intake to almost nothing would not experience hunger or stomach discomfort. The same thing has been observed in total fasting experiments that also produce extreme weight loss in obese patients.

It is interesting that they so drastically and immediately reduced their food intake spontaneously when food reward was taken out of the picture, suggesting that their bodys perceived need for calories was really next to zero, but rather than "elevating" the body fat set point, maybe this kind of hyperpleasurable food was simply overriding it somehow. Maybe the signal to eat less was there all along, but all the brain cared about was getting its pleasure fix from the junk food, and the calories required to maintain the obese state just happened to come along for the ride.

If so it does punch a hole in the "obesity as perceived starvation" theory or that diet-induced leptin resistance is analogous to leptin deficiency, since in a real state of leptin deficiency, ie starvation, you care less about the palatability than the caloric content of food. Practically anything providing calories can taste like heaven when you're truly starving, and that doesn't seem to be the case in obesity.

But it also seems strange because even if the increased calories are just hitching a ride on the need for a pleasure fix, those calories should all the same contribute to the elevated metabolic rate which normally makes the weight gain peter out during overfeeding, so there must be something else going on with the hyperpalatable food that enables some to develop such extreme degrees of obesity.

The big question though is what governs the hypersensibility to palatable foods and how it can be fixed, because going on non-palatable diets like low-carb or low-fat may make you lose weight, but it often makes you even more sensitive to hyperpalatable junk foods and likely to relapse and regain what you lost. Eating to satiety on a whole foods diet that is completely unrestricted in both calories and macronutrients often does completely eliminate this sensitivity to hyperpalatable foods, but I'm not sure why.

I wonder how the complexity of flavors affects things? The traditional Japanese food I've had is very complex and hard to overeat, compared with the simple rewarding combo of sugar and fat in ice cream or something. I was just reading Fermented Foods of the Sudan and it reminded me of how err... many interesting traditional foods taste. Fermented goat and herring anyone?

Did the researhers indicate whether at some point in the flavorless liquid diet the obese eventually spontaneously increased calories to levels more appropriate for their energy expenditure? If so, that would suggest some sort of 'natural' or underlying weight set-point the subjects had, that they eventually began defending.

Second Collden's questions, especially: did the intervention produce a lasting change in set-point? Were the formerly obese able to eat to appetite and unconsciously maintain their reduced fat mass?

Looking forward to the translation into recommendations for today. Thanks Stephen!

(Different David here than the first commenter) Many Japanese foods are the opposite of Western junk food. They are very satisfying but contain few, if any, calories. Take for example miso soup and green tea.

This leads into what I've been thinking about posting since Stephen's first post in this series. I have a very low fructose intake, an excellent omega-3 status, no nutrient deficiencies, and great general health, but I still do need to exert considerable willpower to not over-eat. I've very assiduously taken up any "rewarding" masticating habit that has low or no calories. I drink a lot of unsweetened iced tea, and chew the ice. I chew xylitol gum. I drink black coffee. (If I liked fresh vegetables, I would eat a lot of those, but I only like them cooked)

I also don't grocery shop when hungry, so I am able to resist impulse buys and I don't buy anything that I have had trouble with in the past. For instance, I rarely buy potato chips, as I know I usually can't eat a reasonable amount.

As a result, I manage to only eat when hungry. When I do over-eat, due to the deliciousness of my food, I adjust my portion size down the next time I eat. So far this works for me, with not much hunger and great satisfaction from the food that I do eat.

This is indeed a very interesting study. What really interests me is that the results continued even after the participants returned to the real world where presumably they faced more temptation to overeat calorie-dense foods than they would in a hospital setting. And yet they continued to yield pretty much phenomenal results.

I also think the heightened response to highly palatable food is a learned behavior for many individuals. This helps explain why some are more susceptible to the impact of highly palatable foods while others. In our society, high-stress lifestyles are combined with easy access to extremely flavorful foods. It's easier than ever to set up a reward response to food.

This is fascinating. My diet was extremely bland for a few months because of GI trouble, and I thought my quick, unsought, and seemingly permanent weight loss and lack of appetite was due to the trouble, not so much the diet (except that it was fairly low in fat).

I have to wonder if there's something special about the flavor of junk food that makes rats and people overeat. I am not very satisfied by most junk food. The sweet stuff tastes too sweet, without anything special or satisfying about it. The greasy stuff is too greasy, and the starches puffy and bland.

Because I feel this way and because I view such foods as fairly poisonous, they are easy for me to avoid. I'd much rather have a creme brulee, find that I'm inclined to eat it slowly and am satisfied with a small amount. Sadly, my encounters with creme brulee are fleeting and rare these days.

Back when I ate cookies, and I found myself with some that just weren't so good, my tendency would be to eat more of them, hoping I'd get that special something I was hoping for. If the cookies were really great, one or two would do.

I'd always thought that the different experiences of delicious vs. cheap, mass-produced treats was part of how the French stayed relatively thin, because you can be satisfied with less of something that's truly delicious.

Has anyone ever tried giving the rats really delicious food cafeteria-style? Would they gorge themselves on fine chocolate truffles to the same extent as they would Oreos?

Someone commented on a previous post that junk food flavors are comparable to porn, and I think that's apt, and the compulsive behaviors around them seem similar.

In the end, it's hard to know what recommendations to make based on these studies. People often fall off of diets precisely because they are bland, and a fat-loss diet centered on bland food would be hard to stick to. Though Seth Roberts' idea of having *some* of a day's calories being unconnected to any flavor might be a good compromise.

* As the elderly lose their sense of taste, under-eating and weight loss often become a concern. This fits well with Stephan's arguments here.

* Diet sodas, consumed with a meal, are probably not helping the dieter's goal of eating less.

* When my diet was very bland, I felt sad, even though I did not feel hungry. I missed my past experiences of deliciousness and satisfaction. But if I'd been obese at the outset, maybe I would have been overjoyed at the ease of my weight loss and lack of hunger.

This is truly fascinating. And it suggests a very easy diet to follow that would also be very profitable sell. :) But seriously, I have a few questions-

1. What were the follow-up consequences? Did the weight stay off, or only come back at normal rates? Or was there a rebound?

2. Has a flavorless diet been tried at different macronutrient ratios?

3. How would a normal person without access to industrial food stuffs make a flavorless diet? Every food has a flavor.

----

I seem to be like David #2. I went WAPF years ago and have a whole, unprocessed diet low in Omega-6 and zeroed out in terms of high fructose corn syrup, glutamate, MSG, etc. There's no Froot Loops or Cheeze-its in my diet, but my weight has only stabilized since then. I have lost no weight and my appetite is quite healthy. I still want to eat large meals and easily do so.

Interesting, I appreciate that you repeatedly mention "in susceptible people."

My 9 yo son has friends who are twins, one is a normal 70 lb 3rd grader and his brother is a 130 lb (4'6") 3rd grader. Watching the larger twin eat is astonishing. He chooses the sweetest things in front of him, on taco nite chose only cheese and sour cream for this taco, and will beg for food while the other children play. Put out fruit and raw vegetables, he'll ask for juice and cookies. The normal-weight brother is offered the same foods at home and out, but makes different choices.

So I think, like Collden, the question is how to fix that hypersensitivity in those people.

(Re: Japanese foods. I think there's a strong cultural thing there. They often see food as medicine and have a completely different attitude towards eating. Okinawans have many food-related sayings that encourage good health. Also, the Okinawan/Japanese side of our family frequently criticizes foods for being too oily or too sweet. Much of this is nurture, not nature. I've taught my kids that too. Being kids, they love candy but will often reject a sweet treat for being "too sweet.")

K Black mentions one kind of reward abnormality - constantly seeking high-reward foods. Would a tube-feeding month or to "reset" their brain and allow them to be normal? Or would it just be torture for them as it denies their needs?

Another reward abnormality I am wondering about is low-reward response. I am thinking of myself and David #2 here. What is some people gain weight at a lower reward-point than others? Would that explain why some people get fat eating junk while others don't? Is this a genetic, epigenetic or random condition? Can it also be reset?

More questions than answers now, unless Stephan is holding them back for the big reveal.

I'm no expert on Japanese food, but my impression is it's lower in rewarding qualities than American food. Although they have a lot of umami and salt, white rice until recently provided the large majority of calories (and before white rice, it was starchy tubers, millet, barley and hand-pounded rice). Traditional sushi in Japan has very delicate flavors, not like the deep-fried, mayo and hot sauce filled rolls here. They also eat less sugar than Americans, and I suspect they eat at home more and eat less fast food. Body fatness, heart disease and diabetes are increasing in Japan as their diet industrializes.

Hi Collden,

I didn't see a follow-up. I suspect that if they went back to high-reward eating, their weight would have gone back to its previous level.

Most of the researchers in this field seem to believe what you suggested: that homeostatic and reward/hedonic circuitries are opposing one another, and that the reward/hedonic ones are simply overriding homeostatic control in the current dietary environment, rather than resetting the setpoint. I think it's plausible, although if that were true, it would be difficult to explain why both lean and overweight people (and rats) defend their setpoint so vigorously in situations of voluntary overfeeding. My feeling is that the homeostatic system has more of an ability to protect against upward changes in fat mass than some researchers give it credit for. But time will tell.

Hi Melissa,

More flavorful food is easier to form rewarding flavor-calorie associations with. That's probably why many cultures have super smelly delicacies that smell revolting to people who haven't acquired the taste.

Hi Rob A,

Excellent question. It's hard to know because for most of the experiment, the investigators prescribed a fixed calorie intake of 400 kcal/d. At the end of the experiment, the man was about 200 lbs down from 400, so he wasn't quite lean yet. As you're implying, you'd expect his calorie intake to return to normal after the fat is lost, if the hypothesis is correct. It would have been nice to have that info, but unfortunately I don't. However, I can tell you that when you put an obese rat back on unrefined chow, he will initially eat very little food, and after he has leaned out, his calorie intake will return to normal.

Hi Elizabeth,

I agree, rewarding food is probably used as a coping mechanism for stress, at least in some people. In rodents, certain types of stress can cause long-term fat gain.

Hi Chris,

I'm in! We can use a blended combination of potatoes, kale, beef liver, sardines, goat milk and beets. Mmmm!

I don't think anyone's ever tried a "delicious cafeteria-style diet" on rats, but if you want to do that experiment on a human, I volunteer.

Hi Brock,

I don't know the answer to all your questions, but as for the third one, I don't think the food has to be flavorless, just lower in rewarding qualities. The 60-day potato diet is a good, although somewhat extreme, example of that.

I can't wait 'til we get to the strategies part. I hope you'll be addressing compliance, because if the answer is bland, unpalatable food, it's going to be a tough sell in this hyperpalatable environment!

I’m from Brazil and I would like to share some thoughts with you guys. Basically, that’s how Brazilians following our traditional diet, even though very high in calories, maintain a lean body.

A typical Brazilian meal is composed of rice (unenriched long-grain white rice), beans (pinto, black or black-eyed), some animal protein (meat, sea food or eggs) and some vegetables (cooked or raw). Fat is added to virtually everything: onions and garlic are stir-fried and added to rice, beans and vegetables (they are cooked as 3 separate dishes which are only mixed before eating) and the animal protein is generally prepared with added fat.

Back when my mother was a child (she’s now 59), lard was the main cooking fat. Unfortunately, soybean oil took its place and is widely used nowadays. Not “chez moi”; my family always uses lard. On the other hand, when I’m eating out, I find myself eating soybean oil.

Beans are allowed to soak overnight in plain water and then they are pressure cooked. In the past, slow cooking must have been the only cooking method available, but nowadays pressure cookers are everywhere, plus crockpots aren’t popular in Brazil (I happen to have one but I do admit beans are sometimes pressure cooked at my house).

I’d like to emphasize that the traditional Brazilian diet relies heavily on white rice and beans, which are eaten twice daily (lunch and dinner). No kidding, twice daily! A lot of white rice and beans. I don’t know if brown rice was ever eaten, but I asked my grandparents about it and they used to eat white rice during their childhood. Besides, cassava, cassava flour and cassava starch are also staples in Brazil and they are basically pure starch just like white rice. Guess what: we eat cassava flour along with rice and beans.

I’ve always eaten “the Brazilian way”. Even during my college years in France, I would cook and eat rice and beans on a daily basis. Real French Food is delicious, but as I don’t eat wheat, I had to find something else to stuff myself with.

I’ve always had a lean body. Back when I used to eat sugar, this should be something like 15% of body fat, or less. I quit eating sugar and stuffing myself with lots of fruits and this came down to less than 10% without any change in my activity level (I don’t have any visible/touchable belly fat and I haven’t been exercising properly). And this is also true for every Brazilian that sticks to our traditional diet (white rice and beans daily); they’re certainly not fat. Too bad industrial food is taking over Brazil.

Using nutrition data, I created a recipe called “Brazilian meal”. Actually, that’s what my family had for lunch today. I think I had about 1.5 the content of this meal, which means I had about 1800 calories at lunch. No kidding! My little sister easily ate the 1200 calories provided by this recipe. You can check out my recipe here:

What I found curious about my recipe is that the calorie breakdown is 41% carbs, 43% fats and 16% protein. I thought it would be higher in carbs and lower in fats.

I estimate that I’ve been eating about 4000 calories per day (if not more). A lot of fat and starch. Even though, I keep a lean body and I feel incredibly health. I remember I once tried to cut down on the white rice, but that disturbed my digestion and made me feel like starving all day long. Also, my body temperature dropped.

I don’t think white rice makes people fat. Along with some cassava starch, these are the only “demonized unhealthy processed” foods I eat and they are staples for me. I tried brown rice and found it hard to digest. Moreover, I don’t think traditional Brazilian food isn’t tasty enough to explain its “non-fattening” properties. I do think white rice with a lot of fat is very addictive, but it seems to pass through our bodies without making us fat and helping our digestion.

This is fascinating stuff. One thing I'm wondering about is how all of this relates to the women Gary Taubes describes, the mothers in 3rd World countries who have hungry, emaciated children, but are overweight themselves. Gary speculated that these people are eating a diet that is nutritionally deficient and yet makes the mothers fat - a high carb diet in fact. But if this idea that very palatable food causes incorrect setpoints and thus obesity is right, how could these women be getting fat on what must surely be an unappetizing diet with none of the appeal of modern junk food?

Do you have any reason to believe that rich, industrial flavours would, in addition to making you eat more at the next meal, actually lower or tune down your metabolism to burn less fat? Or is this all just about behavioural patterns adjusting according to these flavours?

In other words, are any other factors at play here besides overeating? Do metabolisms and activity patterns also change according to the flavour of the food?

@PauloI find your experience interesting because you seem to come from a healthy starting point unlike many posters who begin with refractory disease or obesity . My experience is somewhat similar in that I started diet experiments in relatively good health (lean BMI 23) on the advice of my GP to go lower in red meats and increase plant protein, multiple meals/day etc. The result was a very marked deterioration in peridonatal disease, a persistent problem for many years. I reversed the upward trend in carbs over about 5 months and gradually ended up eating a HFLC diet, now 10 months . The improvement in gum health was surprisingly quick and a number of aging bio-markers improved. I have had completely positive results but do not have a convincing explanation that HFLC is the reason and was somewhat concerned about contravening the conventional medical advice. I do not consider theories by the arm-chair scientists (blog owners) really credible beyond accepting that HFLC diet is probably safe in the short term (say 1year). Accordingly I have been experimenting over a fairly wide range of energy (2200-3200Kcal/day) and fat % (60-80) based on careful records. I am now trending down in energy and fat (to 2400Kcal and about 50% F). Over this 15 time period my weight has remained stable (+/- 1lb on 7 day moving average), while my activity level has remained essentially unchanged. I did not suffer any GI distress before (except involuntary flatulence) or after or any other problems except that I now get calf/hamstring cramps on waking unless I take Mg tablets. I would be interested in hearing further from you and others in similar health situation. BTW I am 72yo, how old are you?

There's evidence that people with different epigenetic profiles, due to their what their parents ate, did, and experienced before conception; and exposures to different diet compositions, maternal stress, and chemicals during fetal development and lactation/early infancy, can change a person's later response to different dietary compositions.

Add to that different genetic profiles and various predisposing mutations, and you have a complicated picture on your hands.

I'm interested in this because my experience on a high-fat, low-carb diet was so the opposite of many people's, including yours. It doesn't mean either of is wrong, though dietary absolutists of various stripes would have us believe otherwise.

While reduced taste sensitivity may play a part in unwanted weight loss in the elderly, it is my understanding the the problem is due mainly to increased gut secretion of the appetite suppressing hormone cholestystokinin, and increased sensitivity to same, which results in reduced food intake.

"I also think the heightened response to highly palatable food is a learned behavior for many individuals."

Yes, indeed. As another commenter noted, Japanese do not find Western junk food palatable. Neither do Koreans or Chinese, although sadly, younger Asians are acquiring a taste for fast food pizza, chips, cookies, and other hyperpalatable junk foods and are becoming heavier as a result. I used to shake my head at mainstream media news stories implying or claiming that a love of chili-cheese fries and death-by-chocolate dessert was in our genes. It's not. Food prefences can be unacquired, too. After living many years in East Asia, I lost a desire to eat most dishes that appear on the menus of American casual dining restaurants like TGIFridays, Ruby Tuesdays, and Chilis.

@HelenI agree completely with your statement on epigenetic influences. I would add that there is such a vast space of variables (health environments) both internal and external among individuals that it may be impossible to make useful statements except on a population basis (not useful to individuals) at this time. This is particularly so as it’s probable that the variables are not independent (and not all known) ie close coupled. The external environments eg diet, stress level, exercise are simpler and probably fewer than the internal environment variables eg disease damage, inflammation, lipid peroxidation, ROS etc etc. As far as I know studies which would be useful in this area are probably only of interest to those who are involved in blood analyses, not a large field. Blood analysis technology in my case reveals nothing very useful as it is too broad ie it is a measure of sickness not health. The variability in individual response to the internal/external environments in my opinion is the first order effect on health/nutrition, not fine-tuning of macronutrient ratios or other small effects. Intelligent experimentation is probably the most effective way. Stephan’s objective and insightful presentations are very helpful in designing personal experiments. Also he is good tempered which seems rare on “paleo” blogs. Thank you Stephan.

@Morris; I also found that interesting since I am coming into this discussion with a healthy background and weight.

One thought, though: you said you were 73, and it is very possible your toxin exposure was LESS when you were a child than today. I mean the US was more polluted, but what you were eating might have been cleaner. Less plastic, much less processed food, and less industrial food. When did you have your first french fry? Was it cooked in soybean or beef tallow?

I think this still supports the "Calories In, Calories Out" hypothesis. If you eat fewer kcal, and have the fat mass to support your energy demands, you will burn the fat and lose the weight.

What about fat people who are already consuming few kcal and, yet, are not losing weight?

In lean people, consuming too few kcal will increase sympathetic/ stress control, and will therefore shut down the metabolism, leading to no weight loss, and even weight gain.

Perhaps, based on your post, you would say that, even in fat people, until the fat regulation set-point is reversed completely (with effects extending beyond apatite/satiety, to include ability to release and burn stored fat) eating few kcal will still not result in fat loss. So, for instance, might it be true that eating 400 kcal per day of chocolate slim fats shakes will stress one out and prevent fat loss, while 400kcal of a bland drink with an otherwise similar nutrient profile will lead to fat loss? Would you say that the sweetness of the slim fast shake directly affects, for example, activity of hormone-sensitive lipase, carnitine palmitoyl transferase, uncoupling protein, etc.?

I’m curious what your thoughts are on this.

Either way, I still personally know many obese individuals who have consumed fewer than 1000kcal per day of low-carb paleo foods (relatively bland), and have had their fat loss stall completely after only a few months, long before they got anywhere close to “lean.” Switching to a cyclical carb diet seemed to be the remedy, despite increasing sweet and tasty foods (sweet potatoes, bananas, and occasionally pizza and cookies!) to provide the carbs on high-carb days.

Don't you think that the average fat person 50 years ago was likely fat for different reasons than the reasons the average fat person is fat today? Given how different the cultural/food environment was back then, it seems very likely. This idea leads into something else I hope Stephen will not de-emphasize: the multivariate and uncertain nature of the problem.

Stephen's great past posts about ancestral diets and the wide range of healthy 'primitive' diets have been very useful in deflating others' over-simplified pronouncements on what is a healthy diet and what the causes of obesity and other diseases of modern civilization are. By including the words 'Dominant Factor' in these posts' titles, though, doesn't that seem to fall into the over-certain camp?

I've been enthusiastically following Whole Health Source for over half a year now. One of the things that appeals is how Stephen admits when he is aware of an unknown or uncertainty. However, I'm beginning to feel that even he is susceptible to over-simplification and over-certainty, and that he appears to discount factors that we haven't figured out how to effectively measure.

I understand that to effectively communicate an idea a blog post necessarily must leave out some details, but it seems the time has come for a 'Stephen Guyenet Flowchart of Western Disease, including Obesity'. It would probably have a lot of question marks in it.

to fill our your thesis here you need to fully understand the work of Luis de Lecea from Stanford on hypocretin. I still think your theories are interesting but not supported by the current bench top research in signaling, sleep literature or in metabolic signaling either. No support in my literature either in neurobiology and hypothalamic control. This is clear a recepetor resistant issue as most things seem to be in the hypothalamus. The clinical symptoms are a direct reflection of the receptor resistance. This is an area I follow closely and I don't see any current support for a set point theory at all. It does not mean its not correct but the theory should have some biologic plausibility. However, there is one area where I do think you and Masterjohn are getting warm on is leptin and leptin signalling. Insulin has never been the target. And if it was the be all end all solving type two or type one DM would be a an easy solve with insulin replacement. The ACCORD trial shows truly what an epic failure insulin centric treatment really is. I will continue to watch where you go.......we all can learn from probing. I like your systematic approach and thinking. That is why I read even though I am not a buyer. Dr K

While highly rewarding food may increase food consumption in susceptible people, the theory does not explain the increase in obesity that has occurred in recent decades.

One dietary change that may have contributed to increased obesity is the decrease in consumption of dairy fat due to government dietary guidelines and fad diets.

Low fat dairy results in increased food consumption for two reasons.

First, most low fat dairy contains extra milk protein. Most milk produced in the U.S. is A1 milk which contains beta-casomorphins, opiates that are released on the consumption of casein. It has been found that caso-morphins increase appetite as well a inhibit gastrointestinal motility, secretion, absorption and immune function.

The second reason that low fat dairy products increase food consumption if the lack of fat. Fat is the primary trigger of the appetite suppressing hormone cholecystokinin (CCK) which is secreted in the ileum in response to undigested food and results in decreased food intake. It has been found that dairy fat increases CCK response to a far greater degree than other fats of similar makeup of saturated and polyunsaturated fats. Dairy fat is therefore a highly effective appetite suppressant. (PMID 14652359)

Over 90% of milk and yogurt consumed is non-fat and low fat. The absence of fat and the presence of extra beta-casomorphins in low fat dairy will therefore contribute to increased food consumption.

The same study mentioned above also found that on a low fat diet (20% calories as fat) the insulin response to dairy fat was half of the insulin response of other similar fats. So low fat dairy increases diabetes risk as well as contributing to obesity.

On a high fat diet (38% of calories), insulin response to dairy fat was no different than other fats.

The difference in insulin and CCK response to dairy fat compared to other fats is thought to be due the the makeup of the milk fat globule membrane.

Great series you got going here and is hitting on a few topics that have been top of mind for me lately.

I'd like to throw in a line from neuroplasticity that has been echoing in my brain since I read it in The Brain That Changes Itself (h/t to Todd Becker for alerting me to such an awesome book): "nerves that fire together wire together." Tasty foods that are calorie dense teach the brain to crave these foods. The stronger and more in sync the signals between taste and calories are, the more the brain learns to want those foods over less dense, less tasty foods.

As we experiment with different diets -- specifically ones that require a certain macronutrient content that is substantially different from our current regiment our brains haven't yet fired/wired -- aka learned -- which foods are flavorful and calorie dense on the new diet. Thus we lose weight ... initially. But as we learn the flavorful/dense foods on the new diet (btw low carb is a great example of this) we find weight loss plateaus. Our brains learn to game the diet to maximize flavor and calories.

The solution I'm finding to this problem is to consciously eat blander foods. Also avoid diet drinks generally but specifically around mealtime as they increase the flavors you get with whatever food you're eating. Finally if you find you're eating or craving a certain food regularly (particularly if its calorie dense) there's a good chance your brain has as strong association in play and perhaps it's time to take a break from that food.

Something like this is helping me break through on weight loss plateaus. Also, I'm finding myself asking as I peruse potential snacks or meals, "Is this really calorically dense? Really flavorful?" The more I can answer with the affirmative, the more I figure I should probably choose something else to eat.

What about the Japanese who seem to eat exremely flavorful (e.g, umami flavors) and beautifully presented foods? Their foods seem much more rewarding and tasty than cheetos or pringles, yet they stay thin

Also, umami is just the flavor of protein. You are not going to get fat eating more and more protein, especially considering it take

Also, I don't know too many Westerners that would consider Japanese food to be flavorful. Most hate it unless it is drowned in some sauce. Even my own favorite sushi was unagi which comes with BBQ sauce. It was really the sauce I was craving.

I disagree, I think food reward offers the most compelling explanation for the US/global obesity epidemic. Our diets have progressively industrialized, and food prep has been outsourced to groups whose incentives are to maximize the rewarding/addictive properties of food. They can do that effectively whether the food is high-fat or low-fat.

Hi Justin,

I agree. I think food reward offers a compelling explanation for why people eat less and lose weight initially when their diet changes, but then plateau or rebound even if compliance is good. I've met several people who tried low-carb, it worked great for them once. They went back to their regular diet, gained weight, then went back on a LC diet but it wasn't effective at all the second time. That screams central nervous system adaptation.

Is the mechanism known by which the food reward system affects the lipostat?

My fairly uneducated guess, based on what I understand from your post, is that the reward system could perhaps somehow feed back positively into the orexigenic neurosecretory cells that release NPY, and/or negatively into the anorexienic cells neurosecretory cells that release α-MSH. Doing that would of course cause a shift of energy balance, and therefore cause the point to which the fat mass settles to change.

It would be a bit like changing the voltage of an electrical temperature sensor of a thermostat by putting a battery across the electrical terminals of the sensor. Even though the sensor initially is still measuring the original temperature, the value that is fed into the system is different due to the battery. So the system will eventually settle at a different temperature. (I admit, this analogy has quite some holes in it.)

Another aspect of the food reward system obviously is the time scale of its influence. If the time between meals is shorter than the time it takes for the influence of the food reward system to wear off, then that would mean that leptin, insulin and PYY would never get a chance to do their signalling work "unimpaired". In that case it makes sense that someone stays at a higher fat mass, even though leptin has gone up.

Previously I thought that the only way to interfere with leptin was hormonal (e.g., elevated fasting insulin). But having options to do it neurological does make sense. Perhaps that's also how subcutaneous fat mass is increased due to cold exposure.

Leptin resistance is treated with timing and limiting anything that increases NPY. Food rewards have only do to with the behaviors surrounding food searching. And if your leptin sensitive rewards never matter because apetite is completely controlled. Orexins and hypocretin (where food and cocaine rewards begin and end) answer to leptin receptor sensitivity. Dr. K

Does any of this play into the old stereotype that happier people are fat? Meaning, are their brains more in tune with reward pathways? Would a person is emotionally "stone cold" have an easier time staying lean?

Caesar:Let me have men about me that are fat,Sleek-headed men and such as sleep a-nights.Yond Cassius has a lean and hungry look,He thinks too much; such men are dangerous.Julius Caesar Act 1, scene 2, 190–195

"I'm in! We can use a blended combination of potatoes, kale, beef liver, sardines, goat milk and beets."

Would you suggest that one take a digestive enzyme supplement when on such a diet? After reading Don Matesz's articles on the bioavailability of non-cooked foods I've been considering adding a broad spectrum digestive enzyme supplement to my diet.

This seems especially important in a "tube diet" because of the absence of visual, smell, and chewing cues to start the Cephalic phase. What do you think?

Stephan: I've noticed that if I drop my nightly 2-3 glasses of dry French white table wine (highly palatable) in favor of a large vodka & soda (relatively flavorless but calorie dense like the wine), I can drop some unwanted pounds pretty quickly without making any other changes. I know several others who have experienced this effect. I wonder if food reward offers a better explanation for the effect than whatever differences there may be in the nutrient content of the two beverages. Great blog. Also, go Hoos.

Leptin resistance is treated with timing and limiting anything that increases NPY.

I thought that leptin resistance was still a mystery and that we didn't yet know how to overcome it.

Food rewards have only do to with the behaviors surrounding food searching.

So you don't think that learning that a particular food is delicious will increase actual hunger when we are reminded of it? What do you think? That somehow this learning will only incline us toward eating that particular food when we are already hungry for unrelated reasons? My own experience contradicts this idea.

And if your leptin sensitive rewards never matter because apetite is completely controlled.

Based on your observations, what would you think of a plain (whole milk) yogurt diet? Plain for minimal palatability, whole milk because of the studies that you have posted on the benefits of whole milk.

Milk by itself, has sufficient nutrients, I think, but certainly you could mix in lots of things to add value to the diet. For example, I have been following up on the benefits of dark chocolate. I could put unsweetened chocolate into it. I could grind in liver and (cooked) potato, plus everything else you mention.

All this does is remind me that we're missing the boat by classifying food using macronutrients. I mean, glucose is not lactose is not fructose. They are sugars but really, what a difference in the endproducts from metabolism. Anything that the food industry, or any industry trying to make a profit for that matter, buys into, I just can't trust and this shows that if you can't produce consistent results in the lab with our "recommended" macronutrient classifications then you're screwing up.

For dinner I'll consume whatever the family has cooked after first eating a bowl of rucola salad (bitter and very fibrous salad = very little reward).

I'll report back to see what happens.

In fact Stephan, you seem to have a very wide and loyal readership these days.I encourage you to take advantage of this and organize your own clinical trails using your blog and purpose created websites.

About Me

I'm a writer and science consultant with a background in neuroscience and obesity research. I have a BS in biochemistry and a PhD in neurobiology. I'm the author of "The Hungry Brain: Outsmarting the Instincts That Make Us Overeat".

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